The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.

C57/BL6 mice were administered either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 Cemg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 x 40 mg/kg, s.c., 24 hours between injections; the High dose groups), one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 x 20 mg/kg, s.c., 24 hours between injections; the Low dose groups), and one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered vehicle. Three weeks later, all six groups were tested in motor activity test chambers, followed by injections of L-Dopa (20 mg/kg, s.c.), and then tested over a further 360 min in the activity test chambers. It was found that pretreatment with the selective NA neurotoxin, DSP4, deteriorated markedly the dose-dependent motor activity deficits observed in the vehicle pretreated MPTP treated mice. These 'ultra-deficits' in the spontaneous motor behaviour of MPTP-treated mice were observed over all three parameters: locomotion, rearing and total activity, and were restricted to the 1(st) and 2(nd) 20-min periods. Administration of L-Dopa (20 mg/kg) following the 60-min testing of spontaneous behaviour restored the motor activity of Vehicle + MPTP treated mice (neither the Vehicle + MPTP-Low nor the Vehicle + MPTP-High groups differed from the Vehicle-Vehicle group, here) but failed to do so in the DSP4 pretreated mice. Here, a dose-dependent deficit of L-Dopa-induced motor activity (over all three parameters) was obtained thereby offering further evidence of an 'ultra-deficit' of function due to previous denervation of the NA terminals. The present findings support the notion that severe damage to the locus coeruleus noradrenergic system, through systemic DSP4, disrupts the facilitatory influence on the nigrostriatal DA system, and interferes with the ability of the nigrostriatal pathway to compensate for or recover from marked injury, MPTP treatment.

CD3ζ is a subunit of the CD3 molecule that, until recently, appeared restricted to T cells and natural killer cells. However, experimental studies have demonstrated a role of CD3ζ in dendritic outgrowth in the visual system as well as in synaptic plasticity. Given the increasing evidence for uncharacteristic recapitulation of neurodevelopmental processes in neurodegenerative diseases, in this study, we evaluated brains from subjects with Parkinson's disease and Lewy body dementia for evidence of aberrant CD3 expression. Our data shows marked CD3ζ in association with the α-synuclein containing pathological lesions, i.e., Lewy bodies and Lewy neurites, in the brains of subjects with Parkinson's disease and Lewy body dementia. This finding raises the novel concept of CD3 dysregulation in these disorders as a pathogenic factor and also furthers the increasing evidence that the recall of aberrant neurodevelopmental processes underlies the pathogenesis of neurodegenerative diseases.

Childhood physical abuse (PA) and sexual abuse (SA) interact with monoamine oxidase A (MAOA) gene polymorphism to modify risk for mental disorders. In addition, PA and SA may alter gene activity through epigenetic mechanisms such as DNA methylation, thereby further modifying risk for disorders. We investigated whether methylation in a region spanning the MAOA first exon and part of the first intron was associated with PA and/or SA, MAOA genotype, alcohol dependence, drug dependence, depression disorders, anxiety disorders, and conduct disorder. 114 Swedish women completed standardized diagnostic interviews and questionnaires to report PA and SA, and provided saliva samples for DNA extraction. DNA was genotyped for MAOA-uVNTR polymorphisms, and methylation of a MAOA region of interest (chrX: 43,515,544-43,515,991) was measured. SA, not PA, was associated with hypermethylation of the MAOA first exon relative to no-abuse, and the association was robust to adjustment for psychoactive medication, alcohol and drug dependence, and current substance use. SA and MAOA-uVNTR genotype, but not their interaction, was associated with MAOA methylation. SA associated with all measured mental disorders. Hypermethylation of MAOA first exon mediated the association of SA with current depression, and both methylation levels and SA independently predicted lifetime depression. Much remains to be learned about the independent effects of SA and MAOA-uVNTR genotypes on methylation of the MAOA first exon.

C57/BL6 mice were administered either postnatal iron (Fe2+ 7.5 mg/kg, on postnatal days 10–12) or vehicle, followed by administration of either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 mg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, iron/vehicle treated, DSP4/vehicle treated mice were injected with either a low dose of MPTP (2 × 20 mg/kg, with a 24-hr interval between injections) or vehicle. Behaviour testing took place a further three weeks (spontaneous behaviour and L-Dopa induced) and two weeks (clonidine-L-Dopa induced) later. Postnatal iron administration exacerbated the bradykinesia induced by MPTP and virtually abolished all spontaneous motor activity in NA-denervated mice that were MPTP-treated. Postnatal iron administration reduced markedly the restoration of motor activity by suprathreshold L-Dopa (20 mg/kg) following a 60-min habituation to the test chambers. Pretreatment with DSP4 effectively eliminated the restorative effect of L-Dopa in the MPTP mice. The synergistic effects of co-administration of clinidine (1 mg/kg) with a subthreshold dose of L-Dopa (5 mg/kg) in elevating the motor activity of MPTP mice were reduced markedly by postnatal iron administration, as well as by pretreatment with DSP4. NA-denervation by DSP4, after postnatal iron treatment, totally abolished the activity-elevating effects of the α-adrenoceptor agonist + DA-precursor combination in MPTP mice, and virtually eliminated these effects in saline (non-MPTP) mice. Postnatal iron administration caused enduring higher levels of total iron content in all the groups with an increased level in mice treated with DSP4 followed by MPTP. These divergent findings confirm the direct influence of NA innervation upon dopaminergic functional expression and indicate a permanent vulnerability both in the noradrenergic and dopaminergic pathways following the postnatal infliction of an iron overload.

Wheel-running and treadmill running physical exercise have been shown to alleviate parkinsonism in both laboratory and clinical studies. MPTP was administered to C57/BL6 mice using two different procedures: (a) administration of a double-dose regime (MPTP 2 x 20 or 2 x 40 mg/kg, separated by a 24-h interval), vehicle (saline 5 ml/kg) or saline (vehicle 2 x 5 ml/kg), and (b) administration of a single-dose weekly regime (MPTP 1 x 40 mg/kg) or saline (vehicle 1 x 5 ml/kg) repeated over 4 consecutive weeks. For each procedure, two different physical exercise regimes were followed: (a) after the double-dose MPTP regime, mice were given daily 30-min periods of wheel-running exercise over 5 consecutive days/week or placed in a cage in close proximity to the running wheels for 3 weeks. (b) Mice were either given wheel-running activity on 4 consecutive days (30-min periods) or placed in a cage nearby for 14 weeks. Behavioral testing was as follows: (a) after 3 weeks of exercise/no exercise, mice were tested for spontaneous motor activity (60 min) and subthreshold l-Dopa (5 mg/kg)-induced activity. (b) Spontaneous motor activity was measured on the fifth day during each of the each of the first 5 weeks (Tests 1-5), about 1 h before injections (first 4 weeks), and continued on the 5th days of the 6th to the 14th weeks (Tests 6-14). Subthreshold l-Dopa (5 mg/kg)-induced activity was tested on the 6th, 8th, 10th, 12th and 14th weeks. (b) Mice from the single-dose MPTP weekly regime were killed during the 15th week and striatal regions taken for dopamine analysis, whereas frontal and parietal cortex and hippocampus were taken for analysis of brain-derived neurotrophic factor (BDNF). It was shown that in both experiments, i.e., the double-dose regime and single-dose weekly regime of MPTP administration, physical activity attenuated markedly the MPTP-induced akinesia/hypokinesia in both the spontaneous motor activity and restored motor activity completely in subthreshold l-Dopa tests. Running wheel activity attenuated markedly the loss of dopamine due to repeated administrations of MPTP. BDNF protein level in the parietal cortex was elevated by the MPTP insult and increased further by physical exercise. Physical running wheel exercise alleviated both the functional and biomarker expressions of MPTP-induced parkinsonism.

In traumatic brain injury (TBI), severe disruptions occur in the choroid plexus (CP)-cerebrospinal fluid (CSF) nexus that destabilize the nearby hippocampal and subventricular neurogenic regions. Following invasive and non-invasive injuries to cortex, several adverse sequelae harm the brain interior: (i) structural damage to CP epithelium that opens the blood-CSF barrier (BCSFB) to protein, (ii) altered CSF dynamics and intracranial pressure (ICP), (iii) augmentation of leukocyte traffic across CP into the CSF-brain, (iv) reduction in CSF sink action and clearance of debris from ventricles, and (v) less efficient provision of micronutritional and hormonal support for the CNS. However, gradual post-TBI restitution of the injured CP epithelium and ependyma, and CSF homeostatic mechanisms, help to restore subventricular/subgranular neurogenesis and the cognitive abilities diminished by CNS damage. Recovery from TBI is faciltated by upregulated choroidal/ependymal growth factors and neurotrophins, and their secretion into ventricular CSF. There, by an endocrine-like mechanism, CSF bulk flow convects the neuropeptides to target cells in injured cortex for aiding repair processes; and to neurogenic niches for enhancing conversion of stem cells to new neurons. In the recovery from TBI and associated ischemia, the modulating neuropeptides include FGF2, EGF, VEGF, NGF, IGF, GDNF, BDNF, and PACAP. Homeostatic correction of TBI-induced neuropathology can be accelerated or amplified by exogenously boosting the CSF concentration of these growth factors and neurotrophins. Such intraventricular supplementation via the CSF route promotes neural restoration through enhanced neurogenesis, angiogenesis, and neuroprotective effects. CSF translational research presents opportunities that involve CP and ependymal manipulations to expedite recovery from TBI.

Certain drugs with melanin affinity are known to have caused pigmentary lesions in the eye and skin. This was the basis for the hypothesis that compounds with melanin affinity may cause damage also in other melanin-bearing tissues such as the substantia nigra. The heterogeneity of compounds that binds to melanin is large. Toxins, drugs, and several other compounds have melanin affinity. Compounds showing the highest affinity are mainly organic amines and metal ions. The binding of toxicants to melanin probably protects the cells initially. However, the binding is normally, slowly reversible and melanin may accumulate the toxicant and gradually release it into the cytosol. Several studies indicate that neuromelanin may play a significant role both in the initiation and in the progression of neurodegeneration. MPTP/MPP(+) that has been causally linked with Parkinsonism has high affinity for neuromelanin, and the induced dopaminergic denervation correlates with the neuromelanin content in the cells. This shows that the toxicological implications of the accumulation of toxicants in pigmented neurons and its possible role in neurodegeneration should not be neglected. Extracellular neuromelanin has been reported to activate dendritic cells and microglia. An initial neuronal damage induced by a neurotoxicant that leaks neuromelanin from the cells may therefore lead to a vicious cycle of neuroinflammation and further neurodegeneration. Although there are many clues to the particular vulnerability of dopaminergic neurons of substantia nigra in Parkinson's disease, the critical factors are not known. Further studies to determine the importance of neuromelanin in neurodegeneration and Parkinson's disease are warranted.

In the present study, light and electron microscopy were used to examine heat shock protein (HSP 72kD) expression during acute methamphetamine (METH) intoxication in rats and evaluate its relationships with brain temperature and alterations in a number of other histochemical and morphological parameters. Freely moving rats received METH at the same dose (9 mg/kg, sc) but at different ambient temperatures (23 and 29°C), showing a wide range of brain temperature elevations (37.6-42.5°C); brains were taken for histochemical and morphological evaluations at peak of brain temperature increase. We found that acute METH intoxication induces massive and wide-spread HSP expression in neural and glial cells examined in detail in the cortex, hippocampus, thalamus, and hypothalamus. In each of these structures, the number of HSP-positive cells tightly correlated with brain temperature elevation. The changes in HSP immunoreactivity were also tightly related to alterations in permeability of the blood-brain barrier, acute glial activation, and brain edema assessed by albumin and GFAP immunoreactivity and measuring tissue water content, respectively. While robust and generalized HSP production normally appears to be the part of an adaptive brain response associated with METH-induced metabolic activation, activation of this protective mechanism has its natural limits and could not counteract the damaging effects of oxidative stress, high temperature, and edema-the leading factors of METH-induced neurotoxicity.

The objective of the present study was to evaluate a Monte Carlo feature selection (MCFS) and rough set Rosetta pipeline for generating rule-based models as a tool for comprehensive risk estimates for future Alzheimer's disease (AD) in individual patients with mild cognitive impairment (MCI). Risk estimates were generated on the basis of age, gender, Mini-Mental State Examination scores, apolipoprotein E (APOE) genotype and the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phospho-tau(181) (P-tau) and the 42 amino acid form of amyloid beta (A beta 42) in two sets of longitudinally followed MCI patients (n = 217 in total). The predictive model was created in Rosetta, evaluated with the standard tenfold cross-validation approach and tested on an external set. Features were ranked and selected by the MCFS algorithm. Using the combined pipeline of MCFS and Rosetta, it was possible to predict AD among patients with MCI with an area under the receiver operating characteristics curve of 0.92. Risk estimates were produced for the individual patients and showed good correlation with actual diagnosis in cross validation, and on an external dataset from a new study. Analysis of the importance of attributes showed that the biochemical CSF markers contributed the most to the predictions, and that added value was gained by combining several biochemical markers. Despite a correlation with the biochemical markers, the genetic marker APOE epsilon 4 did not contribute to the predictive power of the model.

The most effective treatment of Parkinson's disease (PD) L-DOPA is associated with major side effects, in particular L-DOPA-induced dyskinesia, which motivates development of new treatment strategies. We have previously shown that chronic treatment with a substantially lower dose of deuterium-substituted L-DOPA (D3-L-DOPA), compared with L-DOPA, produced equal anti-parkinsonian effect and reduced dyskinesia in 6-OHDA-lesioned rats. The advantageous effects of D3-L-DOPA are in all probability related to a reduced metabolism of deuterium dopamine by the enzyme monoamine oxidase (MAO). Therefore, a comparative neurochemical analysis was here performed studying the effects of D3-L-DOPA and L-DOPA on dopamine output and metabolism in 6-OHDA-lesioned animals using in vivo microdialysis. The effects produced by D3-L-DOPA and L-DOPA alone were additionally compared with those elicited when the drugs were combined with the MAO-B inhibitor selegiline, used in PD treatment. The different treatment combinations were first evaluated for motor activation; here the increased potency of D3-L-DOPA, as compared to that of L-DOPA, was confirmed and shown to be of equal magnitude as the effect produced by the combination of selegiline/L-DOPA. The extracellular levels of dopamine were also increased following both D3-L-DOPA and selegiline/L-DOPA administration compared with L-DOPA administration. The enhanced behavioral and neurochemical effects produced by D3-L-DOPA and the combination of selegiline/L-DOPA are attributed to decreased metabolism of released dopamine by MAO-B. The similar effect produced by D3-L-DOPA and selegiline/L-DOPA, respectively, is of considerable clinical interest since D3-L-DOPA, previously shown to exhibit a wider therapeutic window, in addition may reduce the need for adjuvant MAO-B inhibitor treatment.

It has previously been shown that immune complexes (IC) of a given biomarker with class M immunoglobulins (IgM) provide better performances compared to the unbound biomarker in a number of cancer entities. In the present work, we investigated IC of IgM-Abeta as a potential biomarker for Alzheimer's disease (AD). Abeta-IgM concentration has been measured in 75 plasma samples from patients with AD, individuals with mild cognitive impairment (MCI), and healthy age- and sex-matched controls (HC). To characterize the fractions associated with Abeta, pooled plasma samples were subjected to gel-filtration analysis. Size-separated fractions were analyzed for the presence of Abeta using a sandwich ELISA assay. A strong reactivity was observed in the high molecular weight IgM (>500 kDa) and 150 kDa (IgG) fractions indicating that blood Abeta is strongly associated with antibodies. Using an ELISA assay detecting Abeta-IgM complexes, we observed that high levels of Abeta-IgMs were detectable in HC and MCI patients; however, there was no significant difference to the AD group.

The aim of this study was to investigate possible interactions between the gene coding for activating protein-2 beta (AP-2 beta) and psychosocial factors to predict depressive symptoms in adolescents. Two-hundred 16- and 19-year-old adolescents from the county of Västmanland, Sweden, were asked to complete a questionnaire, interviewed about psychosocial risk factors, and genotyped with regard to the transcription factor AP-2 beta intron 2 polymorphism. AP-2 beta genotype interacted significantly both with type of housing and parental separation to predict depressive symptoms. Individuals who were homozygous for the short AP-2 beta allele displayed higher depression scores when psychosocial adversity was taken into account. Amongst carriers of one or two copies of the long allele, there was no difference in depressive symptoms despite differences in psychosocial environments.

Since the pioneering finding of Caspi and co-workers in 2002 that exposure to childhood maltreatment predicted later antisocial behaviour (ASB) in male carriers of the low-activity MAOA-uVNTR allele, frequent replication studies have been published. Two meta-analyses, one in 2006 and the other in 2014, confirmed the original findings by Caspi and co-workers. In the present paper, we review the literature, note some methodological aspects of candidate gene–environment interaction (cG×E) studies and suggest some future directions. Our conclusions are as follows. (1) The direction of the effect in a cG×E model may differ according to the positive and negative environmental background of the population. (2) There is a predictor-intersection problem such that when measuring one type of maltreatment in a person, other kinds of maltreatment often co-occur. Other forms of abuse are implicitly considered in statistical models; therefore, it is difficult to draw conclusions about the effects of timing and the severity of different forms of stressful life events in relation to ASB. (3) There is also an outcome-intersection problem because of the major intersection of ASB and other forms of mental health problems. It is likely that the G×E with MAOA is related to a common unmeasured factor. (4) For the G×E model, in which the effect of the gene on the outcome variable is dependent on other predictor variables, theoretically, hypothesis-driven statistical modelling is needed.

X chromosome inactivation in mammalian females occurs early in embryonic development and renders most genes on the inactive X chromosome transcriptionally silenced. As a consequence, females will display an X chromosomal parent-of-origin mosaicism with regard to which parental allele that is expressed. Some genes however, escape inactivation and will therefore be expressed from both alleles. In this study we have investigated if the X-linked MAO-A gene have bi- or mono-allelic expression. This information would indicate whether or not MAO-A gene dosage could potentially explain the observed gender differences that show functional connections to the serotonin system, such as aggression and impulsiveness. To investigate the X inactivation status of MAO-A we have used primary clonal cell cultures, on which allelic expression was assessed with RFLP analysis. Our results show that the MAO-A gene has mono-allelic expression in these cells. This could have important implications for understanding traits that display gender differences.

Genetic and environmental interactive influences on predisposition to develop alcohol use disorder (AUD) account for the high heterogeneity among AUD patients and make research on the risk and resiliency factors complicated. Several attempts have been made to identify the genetic basis of AUD; however, only few genetic polymorphisms have consistently been associated with AUD. Intermediate phenotypes are expected to be in-between proxies of basic neuronal biological processes and nosological symptoms of AUD. Personality is likely to be a top candidate intermediate phenotype for the dissection of the genetic underpinnings of different subtypes of AUD. To date, 38 studies have investigated personality traits, commonly assessed by the Cloninger's Tridimensional Personality Questionnaire (TPQ) or Temperament and Character Inventory (TCI), in relation to polymorphisms of candidate genes of neurotransmitter systems in alcohol-dependent patients. Particular attention has been given to the functional polymorphism of the serotonin transporter gene (5-HTTLPR), however, leading to contradictory results, whereas results with polymorphisms in other candidate monoaminergic genes (e.g., tryptophan hydroxylase, serotonin receptors, monoamine oxidases, dopamine receptors and transporter) are sparse. Only one genome-wide association study has been performed so far and identified the ABLIM1 gene of relevance for novelty seeking, harm avoidance and reward dependence in alcohol-dependent patients. Studies investigating genetic factors together with personality could help to define more homogenous subgroups of AUD patients and facilitate treatment strategies. This review also urges the scientific community to combine genetic data with psychobiological and environmental data to further dissect the link between personality and AUD.

The importance of an interaction between environment and biological factors for the expression for a particular behaviour is illustrated by results from a series of adolescents in which effects of platelet MAO activity and psychosocial environment on criminality was investigated. In a favourable environment platelet MAO-B activity was not associated with criminality, while a very strong association was found in adolescents from a bad psychosocial environment. Essentially similar findings were obtained when a MAO-A promoter polymorphism was analysed instead of platelet MAO-B activity. In boys, presence of the low functioning allele seemed to be protective against criminal activity in combination with a good environment, while it predisposed for criminality in a bad psycho-social environment. In girls, instead, homozygosity for the high activity MAO-A allele interacted with environment to predict criminality. Possible mechanisms underlying the role of monoamine oxidases for behaviour are discussed.

Genes involved in alcoholism have consensus sites for the transcription factor activator protein (TFAP) 2beta. In the present study, we investigated TFAP-2beta protein levels in the ethanol-preferring alko, alcohol (AA) and the ethanol-avoiding alko, non-alcohol (ANA) rat lines. Furthermore, basal and ethanol-induced TFAP-2beta levels were examined in Wistar rats exposed to different early postnatal environments that are known to affect later ethanol consumption. Taken together, we found differences in brainstem TFAP-2beta protein between the AA and ANA rats.

Immunocytochemistry for transactive response binding protein-43 (TDP43) was assessed in the granular cell layer of the dentate gyrus in 250 cases displaying hippocampal pathology identified by haematoxylin-eosin staining. 18%, nearly one in five displayed TDP43 immunoreactive pathology in the granular cell layer of hippocampus. This percentage increased to 43% when only subjects with hippocampal pathology other than vascular in origin were included. When only subjects with severe Alzheimer's disease-related pathology were included, 42% displayed TDP43-immunoreactive pathology, increasing to 60% when concomitant Alzheimer's disease and alpha-synuclein pathology were present. Within this setting, TDP43-immunoreactive pathology was observed to be present in 6% of subjects with hippocampal pathology but without any cognitive impairment. Our findings justify assessment of TDP43 pathology in every case where a pathological alteration is observed in the hippocampus using a routine stain.

The development of new molecular and neurobiological methods, computer-assisted quantification techniques and neurobiological investigation methods which can be applied to the human brain, all have evoked an increased demand for post-mortem tissue in research. Psychiatric disorders are considered to be of neurobiological origin. Thus far, however, the etiology and pathophysiology of schizophrenia, depression and dementias are not well understood at the cellular and molecular level. The following will outline the consensus of the working group for neuropsychiatric brain banking organized in the Brainnet Europe II, on ethical guidelines for brain banking, clinical diagnostic criteria, the minimal clinical data set of retrospectively analyzed cases as well as neuropathological standard investigations to perform stageing for neurodegenerative disorders in brain tissue. We will list regions of interest for assessments in psychiatric disorder, propose a dissection scheme and describe preservation and storage conditions of tissue. These guidelines may be of value for future implementations of additional neuropsychiatric brain banks world-wide.

Spinal cord injury (SCI) is a devastating disease that leads to permanent disability of victims for which no suitable therapeutic intervention has been achieved so far. Thus, exploration of novel therapeutic agents and nano-drug delivery to enhance neuroprotection after SCI is the need of the hour. Previous research on SCI is largely focused to improve neurological manifestations of the disease while ignoring spinal cord pathological changes. Recent studies from our laboratory have shown that pathological recovery of SCI appears to be well correlated with the improvement of sensory motor functions. Thus, efforts should be made to reduce or minimize spinal cord cell pathology to achieve functional and cellular recovery to enhance the quality of lives of the victims. While treating spinal cord disease, recovery of both neuronal and non-neuronal cells, e.g., endothelia and glial cells are also necessary to maintain a healthy spinal cord function after trauma. This review focuses effects of novel therapeutic strategies on the role of spinal cord microvascular reactions and endothelia cell functions, i.e., blood-spinal cord barrier (BSCB) in SCI and repair mechanisms. Thus, new therapeutic approach to minimize spinal cord pathology after trauma using antibodies to various neurotransmitters and/or drug delivery to the cord directly by topical application to maintain strong localized effects on the injured cells are discussed. In addition, the use of nanowired drugs to affect remote areas of the cord after their application on the injured spinal cord in thwarting the injury process rapidly and to enhance the neuroprotective effects of the parent compounds are also described in the light of current knowledge and our own investigations. It appears that local treatment with new therapeutic agents and nanowired drugs after SCI are needed to enhance neurorepair leading to improved spinal cord cellular functions and the sensory motor performances.

Brief cardiac arrest and survival is often associated with marked neurological alterations related to cognitive and sensory motor functions. However, detail studies using selective vulnerability of brain after cardiac arrest in animal models are still lacking. We examined selective vulnerability of five brain regions in our well-established cardiac arrest model in pigs. Using light and electron microscopic techniques in combinations with immunohistochemistry, we observed that 5, 30, 60 and 180 min after cardiac arrest results in progressive neuronal damage that was most marked in the thalamus followed by cortex, hippocampus, hypothalamus and the brain stem. The neuronal damages are largely evident in the areas showing leakage of serum albumin in the neuropil. Furthermore, a tight correlation was seen between neuronal damage and increase in brain water content and Na(+) indicating vasogenic edema formation after cardiac arrest. Damage to myelinated fibers and loss of myelin as seen using Luxol fast blue and myelin basic protein (MBP) immunoreactivity is clearly evident in the brain areas exhibiting neuronal damage. Upregulation of GFAP positive astrocytes closely corresponds with neuronal damages in different brain areas after cardiac arrest. At the ultrastructural level, perivascular edema together with neuronal, glial and endothelia cell damages is frequent in the brain areas showing albumin leakage. Damage to both pre- and post-synaptic membrane is also common. Treatment with methylene blue, an antioxidant markedly reduced neuronal damage, leakage of albumin, overexpression of GFAP and damage to myelin following cardiac arrest. Taken together, these observations suggest that (a) cardiac arrest is capable to induce selective neuronal, glial and myelin damage in different parts of the pig brain, and (b) antioxidant methylene blue is capable to induce neuroprotection by reducing BBB disruption. These observations strongly suggest that the model could be used to explore new therapeutic agents to enhance neurorepair following cardiac arrest-induced brain damage for therapeutic purposes.

In this study 11 patients with mild Alzheimer's disease (AD) were treated with the cholinesterase inhibitor rivastigmine (mean dose 8.6 +/- 1.3'mg) for 12 months and underwent positron emission tomography (PET) studies of cerebral glucose metabolism (CMRglc) and neuropsychological testing at baseline and after 12 months. An untreated group of 10 AD patients served as control group. While the untreated AD patients showed a significant decline of CMRglc in the temporo-parietal and frontal cortical regions after 12 months follow-up the rivastigmine-treated patients showed no decline in CMRglc in corresponding cortical brain regions. Furthermore, a significant dose-related increase in CMRglc was recorded in the right frontal association region after 12 months rivastigmine treatment. A positive correlation was observed between changes in CMRglc and several cognitive tests in patients receiving higher doses (10.5-12'mg) of rivastigmine. These results suggest a stabilization effect of rivastigmine on CMRglc in mild AD patients receiving long-term rivastigmine treatment.

Huntington's disease is an incurable, adult-onset, autosomal dominant inherited disorder caused by an expanded trinucleotide repeat (CAG). In this study, we describe a Huntington's disease patient displaying clinical symptoms of the behavioural variant of frontotemporal dementia in the absence of tremor and ataxia. The clinical onset was at the age of 36 years and the disease progressed slowly (18 years). Genetic testing revealed expanded trinucleotide CAG repeats in the Huntingtin gene, together with a Glu318Gly polymorphism in presenilin 1. Neuropathological assessment revealed extensive amyloid beta (A beta) aggregates in all cortical regions. No inclusions displaying hyperphosphorylated tau or phosphorylated transactive response DNA-binding protein 43 (TDP43) were found. A high number of p62 (sequestosome 1) immunopositive intranuclear inclusions were seen mainly in the cortex, while subcortical areas were affected to a lesser extent. Confocal microscopy revealed that the majority of p62 intranuclear lesions co-localised with the fused-in-sarcoma protein (FUS) immunostaining. The morphology of the inclusions resembled intranuclear aggregates in Huntington's disease. The presented proband suffered from Huntington's disease showed atypical distribution of FUS positive intranuclear aggregates in the cortical areas with concomitant Alzheimer's disease pathology.

The presence of Abeta(pE3) (N-terminal truncated Abeta starting with pyroglutamate) in Alzheimer's disease (AD) has received considerable attention since the discovery that this peptide represents a dominant fraction of Abeta peptides in senile plaques of AD brains. This was later confirmed by other reports investigating AD and Down's syndrome postmortem brain tissue. Importantly, Abeta(pE3) has a higher aggregation propensity, and stability, and shows an increased toxicity compared to full-length Abeta. We have recently shown that intraneuronal accumulation of Abeta(pE3) peptides induces a severe neuron loss and an associated neurological phenotype in the TBA2 mouse model for AD. Given the increasing interest in Abeta(pE3), we have generated two novel monoclonal antibodies which were characterized as highly specific for Abeta(pE3) peptides and herein used to analyze plaque deposition in APP/PS1KI mice, an AD model with severe neuron loss and learning deficits. This was compared with the plaque pattern present in brain tissue from sporadic and familial AD cases. Abundant plaques positive for Abeta(pE3) were present in patients with sporadic AD and familial AD including those carrying mutations in APP (arctic and Swedish) and PS1. Interestingly, in APP/PS1KI mice we observed a continuous increase in Abeta(pE3) plaque load with increasing age, while the density for Abeta(1-x ) plaques declined with aging. We therefore assume that, in particular, the peptides starting with position 1 of Abeta are N-truncated as disease progresses, and that, Abeta(pE3) positive plaques are resistant to age-dependent degradation likely due to their high stability and propensity to aggregate.

The gene-environment interaction research field in psychiatry has traditionally been dominated by the diathesis-stress framework, where certain genotypes are assumed to confer increased risk for adverse outcomes in a stressful environment. In later years, theories of differential susceptibility, or biological sensitivity, suggest that candidate genes that interact with environmental events do not exclusively confer a risk for behavioural or psychiatric disorders but rather seem to alter the sensitivity to both positive and negative environmental influences. The present study investigates the susceptibility properties of the serotonin transporter-linked polymorphic region (5HTTLPR) in relation to depressive symptoms and delinquency in two separate adolescent community samples: n = 1457, collected in 2006; and n = 191, collected in 2001. Two-, three-, and four-way interactions between the 5HTTLPR, positive and negative family environment, and sex were found in relation to both depressive symptoms and delinquency. However, the susceptibility properties of the 5HTTLPR were distinctly less pronounced in relation to depressive symptoms. If the assumption that the 5HTTLPR induces differential susceptibility to both positive and negative environmental influences is correct, the previous failures to measure and control for positive environmental factors might be a possible explanation for former inconsistent findings within the research field.

beta-Carbolines show structural resemblance to the neurotoxic N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and are metabolized to mitochondrial toxicants. Humans are continuously exposed to low levels of beta-carbolines through cooked food, coffee, alcoholic beverages and tobacco smoke. beta-Carbolines have previously been detected in higher levels in the pigmented substantia nigra than in the cortex of humans. The distribution of 3H-labelled harman and norharman in the brain of pigmented and albino mice and in frogs (a species having neuromelanin) was studied by tape-section and light-microscopic autoradiography. Furthermore, the binding of these beta-carbolines to dopamine-melanin and melanin granules from Sepia officinalis was examined. The results revealed a high affinity binding to melanin and a long-term retention (up to 30 days) in pigmented tissues, including neuromelanin-containing neurons of frogs after a single injection. The role of long-term exposure to food-related beta-carbolines and a retention of these compounds in pigment-containing neurons in the induction of idiopathic Parkinson's disease should be further considered.

beta-Carbolines show structural resemblance to the neurotoxic N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and are metabolized to mitochondrial toxicants. Humans are continuously exposed to low levels of beta-carbolines through cooked food, coffee, alcoholic beverages and tobacco smoke. beta-Carbolines have previously been detected in higher levels in the pigmented substantia nigra than in the cortex of humans. The distribution of 3H-labelled harman and norharman in the brain of pigmented and albino mice and in frogs (a species having neuromelanin) was studied by tape-section and light-microscopic autoradiography. Furthermore, the binding of these beta-carbolines to dopamine-melanin and melanin granules from Sepia officinalis was examined. The results revealed a high affinity binding to melanin and a long-term retention (up to 30 days) in pigmented tissues, including neuromelanin-containing neurons of frogs after a single injection. The role of long-term exposure to food-related beta-carbolines and a retention of these compounds in pigment-containing neurons in the induction of idiopathic Parkinson's disease should be further considered.

The beta-carboline norharman is present in cooked food and tobacco smoke and show structural resemblance to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. C57BL/6 mice were injected subcutaneously with norharman (3 and 10 mg/kg) twice per day for five consecutive days. Eighteen hours after the last dose an increased expression of glial fibrillary acidic protein and fluoro-jade staining were demonstrated whereas the number of tyrosine hydroxylase positive cells were unchanged in the substantia nigra. Two weeks after the last treatment a decreased motor activity was observed whereas cognitive functions remained intact. In cultured PC12 cells norharman treatment induced mitochondrial dysfunction and increased the number of caspase-3 and TUNEL-positive cells. The results demonstrate that norharman induced apoptosis in cultured cells as well as early neurodegeneration, glial activation and sustained motor deficits in mice and suggest that exposure to norharman may contribute to idiopathic Parkinson's disease.

The food contaminant norharman structurally resembles MPTP a compound that selectively damages pigmented brain areas. Both compounds are sequestered and retained in melanin-containing neurons. The aim of the study was to examine whether intracellular melanin can modulate the toxicity of norharman in melanin-loaded PC12 cells. Dopamine melanin protected against norharman-induced upregulation of grp78, activation of caspase 3 and necrosis at low concentrations (5 and 50 µM). In contrast, at a high conentration (500 µM) there was a significantly increased expression of grp78, hsp90 and caspase and a disassociation of melanin aggregates and dispersal of melanin granules to swollen neurite terminals. In human populations, a long-term low-level exposure to toxicants with a high affinity to melanin will probably result in accumulation in melanin-containing neurons in vivo. Our data suggest that accumulation of a neurotoxicant in melanin-loaded cells may lead to increased cell stress, apoptotic signaling and disassociation of melanin aggregates.